Chiral recognition of neutral guests by chiral naphthotubes with a bis-thiourea endo-functionalized cavity

Abstract

Developing chiral receptors with an endo-functionalized cavity for chiral recognition is of great significance in the field of molecular recognition. This study presents two pairs of chiral naphthotubes containing a bis-thiourea endo-functionalized cavity. Each chiral naphthotube has two homochiral centers which were fixed adjacent to the thiourea groups, causing the skeleton and thiourea groups to twist enantiomerically through chiral transfer. These chiral naphthotubes are highly effective at enantiomerically recognizing various neutral chiral molecules with an enantioselectivity up to 17.0. Furthermore, the mechanism of the chiral recognition has been revealed to be originated from differences in multiple non-covalent interactions. Various factors, such as the shape of cavities, substituents of guests, flexibility of host and binding modes are demonstrated to contribute to creating differences in the non-covalent interactions. Additionally, the driving force behind enantioselectivity is mainly attributed to enthalpic differences, and enthalpy -entropy compensation has also been observed to influence enantioselectivity.

Fig. 1. Design of chiral naphthotubes.

a Chemical structures of chiral amide naphthotubes R²,S²-1 and S²,R²-1 in previous work, the chiral centers are highlighted with cyan. b This work: biomimetic design of an endo-functionalized cavity with chiral centers located at the neighborhood of the inward-directing binding sites. The left figure is a cyclic dipeptide (CDP) cyclo-L-Arg-D-Pro complex with a cyclase (PDB: 5z53), the asterisks indicate the chiral centers.

Fig. 2. Synthesis and characterization of chiral naphthotubes.

a Chemical structures of chiral bis-thiourea endo-functionalized syn-configured naphthotubes with R,R and S,S chiral centers, and b anti-configured naphthotubes with R,R and S,S chiral centers, the chiral centers are highlighted with cyan. c X-Ray single crystal structures of R,R-CT2 and S,S-CT2, the acetone molecules binding in the cavities are removed for clarity, the dihedral angles of bis-naphthalene cleft groups are marked with green lines. d Circular dichroism spectra of chiral bis-thiourea endo-functionalized naphthotubes including R,R-CT1, R,R-CT2, S,S-CT1, S,S-CT2 (50 μM in 1,2-dichloroethane, 25 °C).

Fig. 3. Host-guest interaction.

a Chemical structures of the chiral guests. b ¹H NMR spectra (500 MHz, CDCl₃, 0.5 mM, 25 °C) of R,R-CT2, R-5a@R,R-CT2, R-5a, R-5a@S,S-CT2 and S,S-CT2 from bottom to top, host-guest complex ratio is 1: 1, the change of chemical shift are marked with dash line.

Fig. 4. X-Ray single crystal structures of the host-guest complexes.

a S-5a@S,S-CT2, b R-5a@S,S-CT2, c S,S-5b@R,R-CT2, and d S,S-5c@S,S-CT2. Green dotted lines indicate noncovalent interaction including hydrogen bonding, NH···π and CH···π interactions, the solvent molecules are removed for clarity.

Fig. 5. Mechanism investigation of the chiral recognition.

a Variable-temperature ¹H NMR spectra of S,S-CT2 (500 MHz, CDCl₃, 0.5 mM, 25 °C), the temperature decrease from 20 °C to -40 °C. b Circular dichroism spectra of anti-configured chiral naphthotubes with R-5a and S-5a under saturated binding (25 μM in 1,2-dichloroethane, 25 °C). c Energy-minimized structures of R-5a@S,S-CT2, S-5a@S,S-CT2 and d S,S-5c@S,S-CT2, S,S-5c@R,R-CT2, which were obtained by DFT (M06-2x/def2-svp) calculations with the PCM solution model in chloroform at 298 K, the relative energies are shown (M06-2x/ma-def2-tzvpp), the dihedral angles of bis-naphthalene clefts in host-guest complexes are marked with red lines, the butoxy are replaced with methoxy to simplify the calculation.